References of "Liégeois, Jean-François"
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See detail8-Chloro-5-(4-methylpiperazin-1-yl)-11H-pyrido[2,3-b][1,5]benzoxazepine
Dupont, Léon ULg; Liégeois, Jean-François ULg

in Acta Crystallographica Section E-Structure Reports Online (2003), 59(Part 12), 1962-1963

The crystal structure of the title compound, C17H17ClN4O, has been undertaken as part of our studies of dopamine receptors. The oxazepine ring has a boat conformation, while the piperazine ring is in a ... [more ▼]

The crystal structure of the title compound, C17H17ClN4O, has been undertaken as part of our studies of dopamine receptors. The oxazepine ring has a boat conformation, while the piperazine ring is in a normal chair conformation. The dihedral angle between the two aromatic rings that lie on the same side of the oxazepine moiety is 113.99 (7)degrees. There is no hydrogen bonding. [less ▲]

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See detail8-Methyl-6-(4-methylpiperazin-1-yl)-11H-pyrido[2,3-b][1,4]benzodiazepine
Spirlet, Marie-Rose ULg; Graulich, Amaury ULg; Liégeois, Jean-François ULg

in Acta Crystallographica Section E-Structure Reports Online (2003), 59(Part 12), 1990-1991

The conformation of the title compound, C18H21N5, is very similar to that observed in other diaryldiazepine structures such as clozapine and clozapine dihydrobromide. N-H...H hydrogen-bond interactions ... [more ▼]

The conformation of the title compound, C18H21N5, is very similar to that observed in other diaryldiazepine structures such as clozapine and clozapine dihydrobromide. N-H...H hydrogen-bond interactions result in the formation of a dimer. [less ▲]

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See detailJL 13, an atypical antipsychotic: A preclinical review
Ellenbroek, B. A.; Liégeois, Jean-François ULg

in Cns Drug Reviews (2003), 9(1, Spring), 41-56

The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic drug has revealed a close similarity to clozapine, however with some major advantages. JL 13 was characterized as a weak D-2 ... [more ▼]

The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic drug has revealed a close similarity to clozapine, however with some major advantages. JL 13 was characterized as a weak D-2 antagonist, both in vitro and in vivo, with a strong affinity for the D-4 and the 5-HT2A receptors. It has no affinity for the 5-HT2C receptor. In vivo microdialysis experiments in rat showed that JL 13, like clozapine, preferentially increased extracellular dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or striatum. Behavioral studies showed that JL 13, like clozapine, has the profile of an atypical antipsychotic. Thus, JL 13 did not antagonize apomorphine-induced stereotypy nor did it produce catalepsy, but it antagonized apomorphine-induced climbing in rodents. It was inactive against d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced hyperactivity in the mouse. Likewise, in the paw test, it was more effective in prolonging hindlimb retraction time than prolonging forelimb retraction time. Like other antipsychotic drugs, JL 13 reversed the apomorphine- and amphetamine-induced disruption of prepulse inhibition. In a complex temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or any significant motor side effects. In rats and squirrel monkeys JL 13 induced a high degree of generalization (70%) to clozapine. Regarding behavioral toxicology, JL 13 did not produce dystonia or Parkinsonian symptoms in haloperidol-sensitized monkeys. After acute administration, again like clozapine, JL 13 induced only a transient increase in circulating prolactin. Last but not the least, regarding a possible hematological toxicity, unlike clozapine, JL 13 did not present sensitivity to peroxidase-induced oxidation. Moreover, its electrooxidation potential was close to that of loxapine and far from that of clozapine. Taking all these preclinical data into account, it appears that JL 13 is a promising atypical antipsychotic drug. [less ▲]

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See detailModulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry.
Liégeois, Jean-François ULg; Mercier, Frédéric ULg; Graulich, Amaury et al

in Current Medicinal Chemistry (2003), 10(8), 625-47

Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2 ... [more ▼]

Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2+) rises to omega 500 nM. In neurons, this occurs during and after an action potential. Activation of SK channels hyperpolarizes the membrane, thus reducing cell excitability for several tens or hundreds of milliseconds. This phenomenon is called a afterhyperpolarization (AHP). Three subtypes of SK channels (SK1, SK2, SK3) have been cloned and exhibit a differential localization in the brain. SK channels may play a role in physiological and pathological conditions. They may be involved in the control of memory and cognition. Moreover, they are heavily expressed in the basal ganglia (in particular in the substantia nigra, pars compacta) and in the limbic system, suggesting that they may modulate motricity and emotional behaviour. Based on these facts, SK channel subtypes may be a suitable target for developing novel therapeutic agents, but more work is needed to validate these targets. Hence, there is a great need for selective ligands. Moreover, although the risk of peripheral side-effects for SK channel modulators appears to be low, some questions remain to be investigated. Currently, different molecules are known as SK channel modulators. Apamin is a very potent peptidic agent; it produces a strong blockade of these targets which is only very slowly reversible and it has limited selectivity. Dequalinium was found to be an effective blocker. Different chemical modulations on the dequalinium structure led to the discovery of highly potent bis-quinolinium derivatives such as UCL 1684. Other bis-(2-amino-benzimidazole) derivatives are in development. On the other hand, quaternary salts of bicuculline were reported to be effective in inhibiting AHPs. More recent developments on structurally-related molecules revealed that methyl-laudanosine is a new interesting tool for exploring SK channel pharmacology. Finally, a family of compounds has been shown to facilitate SK channel opening. Such compounds may be useful in treating disorders involving neuronal hyperexcitability. [less ▲]

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See detailNew pyridobenzodiazepine derivatives: Modifications of the basic side chain differentially modulate binding to dopamine (D-4.2, D-2L) and serotonin (5-HT2A) receptors
Liégeois, Jean-François ULg; Eyrolles, L.; Ellenbroek, B. A. et al

in Journal of Medicinal Chemistry (2002), 45(23), 5136-5149

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol ... [more ▼]

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K-i > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D-4.2 and 5-HT2A receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives (21, 36) possessed less affinity in comparison with the N-metbylpiperazine analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidine nucleus as obtained in azabicyclo [3.2.1] octane derivatives (23, 38) involved a slight reduction of the affinity at D-4.2 and 5-HT2A receptors while the affinity at D-2L receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D-4.2 receptors but some of these molecules (24, 25, 41) presented a significant 5-HT2A binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D-4.2 and 5-HT2A affinity (K-i = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties. [less ▲]

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See detailMethyl-laudanosine: A new pharmacological tool to investigate the function of small-conductance Ca2+-activated K+ channels
Scuvée-Moreau, Jacqueline ULg; Liégeois, Jean-François ULg; Massotte, Laurent ULg et al

in Journal of Pharmacology and Experimental Therapeutics (The) (2002), 302(3), 1176-1183

Small-conductance Ca(2+)-activated K(+) channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating ... [more ▼]

Small-conductance Ca(2+)-activated K(+) channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-laudanosine, and ethyl-laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC(50) values of 152, 15, and 47 microM, respectively. The benzyl and butyl derivatives were less potent. Methyl-laudanosine had no effect on the I(h) current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABA(A) receptors. Interestingly, 100 microM methyl-laudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC(50) 4 microM) is superior to its affinity for muscarinic (IC(50) 114 microM) and neuronal nicotinic (IC(50) > or =367 microM) receptors. Methyl-laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models. [less ▲]

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See detail5-HT2A receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner
Liégeois, Jean-François ULg; Ichikawa, J.; Meltzer, H. Y.

in Brain Research (2002), 947(2), 157-165

Combined serotonin (5-HT)(2A) and dopamine (DA) D-2 blockade has been shown to contribute to the ability of atypical antipsychotic drugs (APDs) to increase DA release in rat medial prefrontal cortex (mPFC ... [more ▼]

Combined serotonin (5-HT)(2A) and dopamine (DA) D-2 blockade has been shown to contribute to the ability of atypical antipsychotic drugs (APDs) to increase DA release in rat medial prefrontal cortex (mPFC). We provide additional support for this hypothesis by examining the effect of the selective 5-HT2A antagonist M100907 plus haloperidol, a potent D, antagonist APD, on DA release in the mPFC and nucleus accumbens (NAC). Haloperidol (0.01-1.0 mg/kg) produced an inverted U-shaped increase in DA release in the mPFC, with a significant increase only at 0.1 mg/kg. Haloperidol (0.1 and 1.0 mg/kg) significantly increased DA release in the NAC. M100907 (0.1 mg/kg) by itself had no effect on DA release in either region. This dose of M100907 potentiated the ability of low (0.01-0.1 mg/kg), but not high dose (0.3-1.0 mg/kg) haloperidol to increase mPFC DA release, whereas it abolished the effect of both 0.1 and 1.0 mg/ka haloperidol on NAC DA release. These results suggest that the relatively higher ratio of 5-HT2A to D-2 antagonism may contribute to the potentiation of haloperidol-induced mPFC DA release, whereas 5-HT2A antagonism can diminish haloperidol-induced NAC DA release, even when combined with extensive D, antagonism, which may not be synergistic with 5-HT2A antagonism in the mPFC. (C) 2002 Elsevier Science B.V. All rights reserved. [less ▲]

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See detailMinimal effects of JL 13, a pyridobenzoxazepine derivative with an antipsychotic potential, on circulating prolactin levels in male rats
Liégeois, Jean-François ULg; Bruhwyler, J.; Hendrick, J. C. et al

in Neuroscience Letters (2002), 319(1), 49-52

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal ... [more ▼]

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal injection in gentled male rats in comparison with clozapine and haloperidol. A total of 30 or 150 min after administration, whole blood was collected for preparing serum samples. Prolactin was quantified by radioimmunoassay method. At 30 min, JL 13 like clozapine, increased prolactin concentration only at the higher dose (30 mg/kg) while haloperidol at both tested doses induced a dramatic increase of prolactin concentration. At 150 min after injection, only haloperidol (0.3 mg/kg) significantly increased serum prolactin level. This minimal effect on prolactinemia reinforces the similarity of clozapine and JL 13 regarding the atypical antipsychotic profile. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. [less ▲]

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See detail8-Chloro-6-(3-dimethylaminopropylamino)-11H-pyrido[2,3-b][1,4]benzodiazepine
Dupont, Léon ULg; Eyrolles, Laurence; Evrard, Guy et al

in Acta Crystallographica Section E-Structure Reports Online (2002), 58(Part 1), 69-71

The crystal structure determination of the title compound, C17H20ClN5, has been undertaken as part of studies on antipsychotic drugs. Its structure is compared with that of clozapine (C18H19ClN4), a well ... [more ▼]

The crystal structure determination of the title compound, C17H20ClN5, has been undertaken as part of studies on antipsychotic drugs. Its structure is compared with that of clozapine (C18H19ClN4), a well known atypical antipsychotic drug. The side chain is more flexible than in the N-methylpiperazine analogues, but its folding is influenced by an intramolecular N-H . . .N hydrogen bond. The distances between the N-distal atom, a possible pharmacophore, and the centres of the two aromatic rings are significantly shorter than in clozapine. The crystal packing involves one N-H . . .N intermolecular hydrogen bond. The title compound showed no affinity for the receptors tested. [less ▲]

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See detailLa clozapine, source d'inspiration pour les pharmacochimistes, les pharmacologues et les psychopharmacologues
Liégeois, Jean-François ULg

Thèse d’agrégation de l’enseignement supérieur (2002)

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See detailLe controle du reseau vasculaire cutane
Damas, Jacques ULg; Garbacki, Nancy ULg; Liégeois, Jean-François ULg et al

in Revue Médicale de Liège (2001), 56(12), 846-9

In man, three kinds of sympathetic neurons reach the skin. Some cholinergic neurons stimulate the sweat glands, they are excited by temperature-regulating centers. Adrenergic neurons release noradrenaline ... [more ▼]

In man, three kinds of sympathetic neurons reach the skin. Some cholinergic neurons stimulate the sweat glands, they are excited by temperature-regulating centers. Adrenergic neurons release noradrenaline and ATP to reduce cutaneous blood flow while cholinergic neurons release acetylcholine and a co-transmitter to dilate skin blood vessels. The excitation of both latter types of nerve cells depends on influences from temperature-regulating centers, baroreceptors and exercise. Moreover, in cutaneous blood vessels, a synthesis of NO is enhanced by an increase of body temperature and overall by direct heating of the skin. Burns are associated with axon reflexes and release of inflammatory mediators. The involvement of these various influences is described. [less ▲]

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See detailElectrooxidation Potential as a Tool in the Early Screening for New Safer Clozapine-Like Analogues
Mouithys-Mickalad, Ange ULg; Kauffmann, J. M.; Petit, C. et al

in Journal of Medicinal Chemistry (2001), 44(5), 769-76

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine fumarate (9 ... [more ▼]

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine fumarate (9), with a clinical or psychopharmacological profile similar to that of clozapine. However, when developing new derivatives, the designers are discouraged by the development of clozapine-induced agranulocytosis. Different researchers have raised the role played by the oxidizability of the molecule in such a deleterious effect. In the present paper, we examined the oxidation profile (direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to clozapine, some of them being described as putative antipsychotic. The oxazepine derivative 7, unlike the other diazepine derivatives (6, 10--12), was not readily oxidized. Using a statistical predictive model for hematotoxicity previously described, 7 was found in the cluster of potentially nontoxic compounds while diazepine derivatives 6 and 10-12 were classified as potentially toxic compounds. Among these original compounds, 7, which presents a preclinical clozapine-like profile and a low sensitivity to oxidation, could be a promising antipsychotic candidate with low side effects. Considering the tricyclic derivatives examined so far, some elements of structure-oxidation relationship (SOR) might be pointed out. Regarding the nature of the tricyclic ring substituent, from the most to the least sensitive to oxidation, the sequence was as follows: HO > Cl > CH(3)O > CF(3)SO(2)O. The nature of the tricyclic ring influenced also the sensitivity to oxidation; the diazepine moiety appeared to be the most reactive ring compared to oxa- and thiazepine congeners. These parameters could be advantageously integrated in the early design of new safer clozapine-like analogues. [less ▲]

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See detailAbout the relationship between the kallikrein-kinin system and insulin
Damas, Jacques ULg; Liégeois, Jean-François ULg

in Current Topics in Peptide and Protein Research (2001), 4

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See detailNovel inhibitors of the sodium-calcium exchanger: benzene ring analogues of N-guanidino substituted amiloride derivatives
Rogister, F.; Laeckmann, D.; Plasman, P.-O. et al

in European Journal of Medicinal Chemistry (2001), 36

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See detailScopolamine reduces clozapine-induced dopamine release in rat striatum
Liégeois, Jean-François ULg; Ichikawa, J.; Meltzer, H. Y.

in O'Connor, W. T.; Lowry, J. P.; O'Connor (Eds.) et al Monitoring Molecules in Neuroscience - Proceedings of the 9th International Conference on In Vivo Methods (2001)

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See detailThe effects of JL 13, a pyridobenzoxazepine with potential atypical antipsychotic activity, in animal models for schizophrenia
Ellenbroek, Bart; Liégeois, Jean-François ULg; Bruhwyler, Jacques et al

in Journal of Pharmacology and Experimental Therapeutics (2001), 298

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See detailThe behavioral effects of acute and chronic JL 13, a putative antipsychotic, in Cebus non-human primates
Casey, Daniel; Bruhwyler, Jacques; Delarge, Jacques et al

in Psychopharmacology (2001), 157

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See detailPreparation of mebendazole HP-beta-cyclodextrin complexes using water-soluble polymers and organic acids
Alvarez, Covadonga; Van Hees, Thierry ULg; Piel, Géraldine ULg et al

in STP Pharma Sciences (2001), 11(6), 439-442

Mebendazole (MBZ) is a carbamate derivative with an aminobenzimidazole structure. It possesses antihelminthic properties and is particularly insoluble in water. In order to increase its aqueous solubility ... [more ▼]

Mebendazole (MBZ) is a carbamate derivative with an aminobenzimidazole structure. It possesses antihelminthic properties and is particularly insoluble in water. In order to increase its aqueous solubility, hydroxpropyl-beta-cyclodextrin (HP-beta-CD) was used in combination with water-soluble polymers (polyvinylpyrrolidone or hydroxypropymethyl cellulose) and different organic acids (citric or tartaric). Increased solubility was observed on heating the mixture. The effects of the time and temperature of the heating process on drug solubility and stability were investigated. The results clearly show that the best conditions for increasing solubility and limiting degradation of MBZ is to heat a combination of MBZ, HP-beta-CD (200 mM), tartaric or citric acid (50 mM) and HPMC (0.1% w/v) in a water-bath at 95degreesC for 60 min. This method increases solubility to about 680 mug/ml and limits degradation to 2.5%. [less ▲]

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